Project Summary/Abstract: (30 lines maximum) The overall goal of this proposal is to develop genetic and pharmacological interventions that improve Sirt6 activity in order to extend healthy life span and to delay the onset and progression of Alzheimer?s Disease (AD). AD and other Related Dementias (ADRD) affect well over 5 million people in the United States. By mid-century, these numbers are predicted to at least triple. Despite this, there are no effective treatments for these devastating illnesses. Recent observations link the onset and progression of AD to a loss of chromatin stability and disruption of the epigenome and transcriptome. Sirt6 is involved in the maintenance of chromatin, the epigenome, the transcriptome and longevity. A decrease in Sirt6 expression is coincident with a deterioration in the maintenance of chromatin and normal transcription and evidence, including our preliminary studies, indicates that increasing Sirt6 activity is neuroprotective. We hypothesize that a decline in Sirt6 activity with age promotes dysregulation of the epigenome, resulting in chromatin and transcriptional instability that contributes to age- related diseases including AD. We propose that interventions that improve Sirt6 function can extend healthy life span and delay the onset and progression of AD. We will use genome-wide approaches and genetic interventions that alter the activity of Sirt6 and extend life span in order to establish the role of Sirt6 in maintenance of the epigenome, the transcriptome, life span and the onset and progression of AD in the fly model. Through a combination of these studies we will define the specific genetic elements that make up the Sirt6 life span extending pathway to provide new targets for enhancing Sirt6 activity for healthy life span and to delay the onset and progression of AD. We will test the hypotheses that: (i) increasing the activity of Sirt6 alters the epigenome and the transcriptome to improve healthy life span; (ii) genes essential for Sirt6-related life span extension define a molecular genetic pathway providing targets for interventions to improve healthy longevity and AD; and (iii) enhancing the activity of Sirt6 can delay the onset and progression of AD. We will use a number of different approaches to determine the role of Sirt6 in preventing genomic and transcriptomic instability and extending healthy life span, and its potential for delaying the onset and progression of AD. Genetic approaches and pharmacological manipulations that increase life span will be used to examine the role of Sirt6 on the epigenome and transcriptome through ChIP-seq (H3K9ac), ATAC-seq, and RNA-seq. New proteins that interact with, and are functionally responsible for Sirt6 longevity, will be isolated using IP-MS, a deficiency screen, and an unbiased mutagenesis, and their effect on enhancing the activity of the Sirt6 pathway will be confirmed using genetic epistasis life span experiments. Genetic tools and pharmacological agents, both presently available as well as additionally to be identified through these studies, will be directly used to boost Sirt6 activity in the context of well-established models of AD in the fly.